(1-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl compounds

ABSTRACT

(1-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl-sulfides, sulfoxides and -sulfones of the formula I   in which R1 represents methyl or ethyl, R2 represents a hydrogen atom or methyl, Z represents a sulfide group (-S-), a sulf-oxide group (-SO-) or a sulfone group (-SO2-), which may be linked with the pyridine ring in the 2-, 3- or 4-position, and in which R3 represents a halogen atom, a cyano or nitro group, and process for preparing them. The compounds are active against trichomonas and amebas.

Winkelmann et al.

[54] (l-ALKYL-5-NlTR()-IMIDAZOLYL-2- ALKYL)-PYRIDYL COMPOUNDS [75] lnventors: Erhardt Winkelmann, Kelkheim,

Taunus; Wolfgang Raether, Dreieichenhain, both of Germany [73] Assignee: Hoechst Aktiengesellschaft,

Frankfurt am Main, Germany [22] Filed: Nov. 14, 1974 [2]] Appl. No.: 523,917

[30] Foreign Application Priority Data Nov. 16, 1973 Germany 2357277 [52] US. Cl.... 260/294.8 F; 260/294.8 G; 260/309; 424/263 [51] Int. Cl. C07D 401/12 [58] Field of Search 26O/294.8 G, 294.8 F

[56] References Cited UNITED STATES PATENTS 3,635,995 l/l972 Manning 260/2948 G Nov. 25, 1975 Primary E.\aminerHenry R. Jiles Assistant Examiner-Robert W. Ramsuer Attorney, Agent, or FirmCurtis, Morris & Safford [57] ABSTRACT (l-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl-sulfides, -sulfoxides and -sulfones of the formula I in which R'represents methyl or ethyl, R represents a hydrogen atom or methyl, Z represents a sulfide group (S--), a sulf-oxide group (-80-) or a sulfone group (SO which may be linked with the pyridine ring in the 2-, 3- or 4-position, and in which R represents a halogen atom, a cyano or nitro group, and process for preparing them. The compounds are active against trichomonas and amebas.

8 Claims, N0 Drawings (l-ALKYL-S-NITRO-lMlDAZOLYL-Z-ALKYL PYRIDYL COMPOUNDS The use of l-( 2-hydroxyethyl)-2-methyl-5- nitroimidazole (Metronidazole) in the combat against protozoan diseases such as trichomoniasis and amebiasis is known.

The present invention relates to novel (l-alkyl-S- nitroimidazolyl-Z-alkyl)-pyridyl-sulfides, -sulfoxides and -sulfones of the formula I M N (I) in which R represents methyl or ethyl, R represents hydrogen or methyl, Z is a sulfur bridge (S), a sulfoxide group (SO) or a sulfone group (SO and may be linked to the pyridine ring in the 2-, 3- or 4- position and in which R is fluorine, chlorine, bromine or iodine, cyano or nitro.

Among the compounds of the formula 1, those are preferred in which the substituent R is in the 3- or 5- position of the pyridine ring and the substituent Z is in the 2- or 4-position of the pyridine ring.

The invention furthermore relates to a process for preparing the (l-alkyl-5-nitro-imidazolyl-Z-alkyl)-pyridyl-sulfides, -su1foxides and -sulfones of the formula 1, which essentially consists in a. reacting a l-alkyl-2-halogenoalkyl-5-nitroimidazole of the formula II CH-Z N l CH-X (II) 0 w i; L

in which R and R have the meanings given for formula I and X represents halogen or acyloxy, preferably acetoxy, propoxy, butoxy, benzoyloxy, benzyloxy or tolyloxy, or an arylsulfonic acid ester group, preferably a benzene-sulfonic acid ester group, a toluene-sulfonic acid ester group of a naphthalene-sulfonic acid ester group, with a mercaptopyridine or an alkali metal salt or ammonium salt thereof of the formula III in which R has the meaning given for formula I and Y is hydrogen, an alkali metal, in particular sodium or potassium, or ammonium, or

with a halogenopyridine of the formula V in which X and R have the meanings given above,

and optionally oxidizing the sulfide compound of the formula I so obtained into a sulfoxide or sulfone.

As starting substances of the formula II, there may be used, for example l-methyl-, l-ethyl-2-chloro-, -2- bromo-, -2-iodomethylor 1-methyl-, 1-ethyl-2-chloro -2-bromo-, -2-iodo( l-ethyl)-5-nitro-imidazole, 1- rnethyI- or 1-ethyl-2-acetoxy-5-nitro-imidazoleor 1- methylor l-ethyl-2-benzeneor -2-toluenesulfonic acid ester.

As starting substances of the formula-Ill, there may be used, for example, 2-mercapto-3-, -4-, -5-, -6-fluoro- -chlpro-, -bromoor -iodo-pyridine, 2-mercapto-3-, -4-, -5-, -6-cyanoor -nitro-pyridine, 3-mercapto-2-, -4-, -5-, -6-fluoro-, -chloro-, -bromoor -iodo-pyridine, 4-mercapto-2-, -3-fluoro-, -chloro-, -bromoor -iodopyridine, 4-mercapto-2-, -3-cyanoor -nitropyridine.

Instead of the mentioned mercapto compounds, there may also be used their alkali metal salts or ammonium salts, or mercaptan formers such as the isothiouronium salts.

As starting substances of the formula IV, there may be used, for example, l-methyl-, l-ethyl-2-mercaptomethylor l-methyl-, l-ethyl-2-mercapto-(l-ethyl)-5- nitro-imidazole or the alkali metal salts or ammonium salts thereof, or mercaptan formers such as the isothiouronium salts.

As starting substances of the formula V, there may be used, for example, all the compounds indicated for formula III, in which, however, the mercapto group is replaced by fiuorine, chlorine, bromine or iodine, or an acetoxyor -benzeneor -toluenesulfonic acid ester grouping.

The 1-alkyl-2-chloroalkyl-5-nitro-imidazoles of the formula II used as starting substances are obtained by reaction of l-alky1-2-hydroxya1kyl-5'nitro-imidazoles with thionyl chloride, and may then be converted, if desired, into the corresponding fluoro-, bromoor iodocompounds by reaction with other metal halides.

The l-alkyl-2-acyloxy-alkyl-5-nitro-imidazoles or 1- alkyl-2-(arylsulfonyloxyalkyl)-5-nitro-imidazoles of the formula ll furthermore used as starting substances are obtained by the reaction of l-alkyl-2-hydroxyalkyl-5- nitro-imidazoles with an acid anhydride or acide chloride such as acetanhydride or acetyl chloride or with aryl-sulfonic acid chloride such as 4-toluenesulfonic acid chloride.

The mercapto-pyridines of the formula III used as starting substances are obtained from corresponding halogeno-pyridines by the reaction with hydrogen sulfide or, in the case of cyanopyridines, by diazotization 3 of the corresponding amino-cyanopyridines and reaction of the diazonium salt so obtained with alkali metal xanthogenates.

The l-alkyl-2-mercapto-alkyl-5-nitroimidazoles of the formula IV used as starting substances are obtained from corresponding 2-halogeno-alkylpyridines by the reaction with hydrogen sulfide.

The halogeno-pyridines of the formula V used as starting substances are prepared from corresponding hydroxy compounds with phosphorus halides.

The two variants (a) and (b) of the process of the invention are suitably carried out with equimolar amounts of the respective starting substances, advanta' geously in a solvent or dispersing agent. 1f the free mercapto compounds of the formula 111 or IV are used, it is preferred to work in a polar solvent; lf salts of these compounds are used, it is preferred to use non-polar solvents.

As non-polar solvents, there may be used, for example, benzene, toluene, xylene, chloro-benzene. As polar solvents, there may be used, for example alcohols such as methanol, ethanol, propanol, butanol, methoxyethanol or ketones such as acetone, methylethylketone, methylbutyl-ketone, furthermore pyridine, picoline, quinoline, dimethylformamide, dimethylacetamide, N- methylpyrrolidone, tetramethyl-urea, hexamethylphosphoric acid triamide or dimethylsulfoxide.

The reaction temperatures may generally be between and 150 C, preferably between 30 and 100 C. 1n the case of reactions in polar solvents, the lower temperature ranges are sufficient, while in the case of reactions in non-polar solvents the higher temperatures are more suitable. Depending on the temperature, the reaction tims are in the range of from a few minutes to several hours.

If free mercapto compounds of the formula III and IV are used, it is advisable to apply an acid-binding agent. As acid-binding agents, there may be used bases such as triethylamine or pyridine, and alkali metal and alkaline earth metal carbonates; bicarbonates, hydroxides and alkoxides, for example the -methoxides, -ethoxides and -butoxides:

Isolation of the products of the invention is carried out according to the usual methods by removal by distillation of the solvent used or dilution of the reaction solution with water. The purification may also be carried out by recrystallization from a suitable solvent or mixture of solvents.

The sulfides of the formula I (A -S-) obtained by one of the described process variants (a) or (b) may be converted into the corresponding sulfoxides (A SO) or sulfones (A '-SO by oxidation.

The oxidations are suitably effected using oneor two-fold amounts of an oxidizing agenLThe treatment of the sulfides with one molar equivalent of oxidizing agent yields sulfoxides, the treatment with two molar equivalents yields sulfones. As oxidizing agents, there may be used, for example hydrogen peroxide or peracids, for example per-acetic acid, per-trifluoroacetic acid or metachloro-perbenzoic acid, as well as nitric acid or chromic acid, or the salts thereof, furthermore per-manganates, hypochlorites, perchlorates, periodates and nitrogen oxides.

The oxidation reactions are advantageously carried out in a solvent or dispersing agent.

For this purpose, there are especially suitable those solvents which are not attacked by the oxidizing agent, for example acetic acid, trifluoroacetic acid. If per-benzoic acid is used, there may also be used methylene g chloride or chloroform as solvent.

The oxidation reactions which are intended to yield sulfoxides are generally carried out at temperatures between 10 C and 30 C. The sulfones are generally obtained at oxidation temperatures between 50 and 100 C. The sulfonyl compounds may also be prepared by oxidation of the corresponding sulfonyl compounds I with the oxidizing agents mentioned for such a purpose at elevated temperature.

Depending on the temperatures used and on the. de- I sired final product, the oxidation reaction times are in the range of from a few minutes to several hours.

Isolation of the products of the invention is carried out by dilution of the reaction solution with water and simultaneous precipitation or evaporation of the organic solvent under reduced pressure. Purification may also be carried out by recrystallization from .a suitable solvent or mixture of solvents.

the known Metronidazole.

Therefore, the novel compounds of the formula 1 are A suitable for combating protozoan diseases in man and animals, for example those provoked by infections by T. vaginalis and E. histolytica.

The novel compounds may be applied either per orally or locally. For oral administration, the. compounds are applied in general in the form of tablets or capsules which contain, per daily dose, about 10 to 750 mg of the active substance with the usual addition of a diluting and/or extending agent. For local administration, there may be used gels,'creams, ointments or sup V positories.

The following Examples illustrate the invention.

EXAMPLES l. l-Methyl-2-( 5-bromopyridyl-2-thiomethyl- )-5 nitro-imidazole 2.3 g (01 moles) of metallic sodium were dissolved in small portions in 50 ml of anhydrous methanol. lnto this sodium methylate solution, there were introduced 19.0 g (0.1 mole) of 2-mercapto-5-bromo-pyridine,

dissolved in ml of anhydrous methanol, and the solu- 5 tion was evaporated under reduced pressure. The residue was combined with a solution of 17.55 g (0.1 mole) of l-methyl-2-chloromethyl-5-nitro-imidazole in ml of dimethylacetamide and the reaction mixture was heated for 1 hour to 1 10 C. After cooling, the solution was combined with water until crystallization began- The final product was filtered off and recrystallized from ethanol with addition of charcoal. 26.5 g of lmethyl-2-(5-bromopyridyl-2-thiornethyl)-5- nitroimidazole (corresponding to 80% of the theory) in g g the form of yellowish crystals melting at 116 C were obtained. In the same manner, there'were obtained with good yields:

2. 1-methyl-2-(5-cyanopyridyl-Z-thiomethyl) 5- nitro-imidazole, Fp., C, from l-methyl-2- chloromethyl-5nitro-imidazole and 2-mercapto-5- cyanopyridine.

3. I-methyl-2-(5-nitropyridyl-2-thiomethyl)-5-nitroimidazole, Fp. 142C, from l-methyl-2-chloromethyl S-nitro-imidazole and Z-mercapto-S-nitropyridine.

4. l-ethyl-2-(5-nitropyridyl-Z-thiomethyl)-5-nitroimidazole, Fp. 63C, from l-ethyl-2-chloromethyl-5- 123. 1-ethyl-2-( 3-bromopyridyl-4-sulfonyl-methyl)- S-nitro-imidazole 124. l-methyl-2-[ 3-fluoropyridyl-2-sulfonyl-( 1- ethyl)]-5-nitro-imidazole 125. 1-methyl-2-[3-chloropyridyl-2-sulfonyl-(1- ethyl) ]-5-nitro-imidazole 126. 1-rnethyl-2-[ 3-bromopyridyl-2-sulfonyl-( 1 ethyl)]-5-nitro-imidazole 1-methyl-2-[5-fluoropyridyl-3-sulfonyl-( 1-ethyl)]-5- nitro-imidazole 128. l-methyl -2-[ 5-chloropyridyl-3-sulfonyl-( 1- ethyl)]-5-nitro-imidazole 129. 1-methyl-2-[ 5-bromopyridyl-3-sulfonyl-( lethyl)]-5-nitro-imidazole 130. l-methyl-2-[ 3 -fluoropyridyl-4-sulfonyl-( 1- ethyl)]-5-nitro-imidazole 131 l-methyl-2-[ 3 -chloropyridyl-4-sulfonyl-( 1- ethyl)]-5-nitro-imidazole 132. l-methyl-2-[ 3-bromopyridyl-4-sulfonyl-( l-' ethyl)]-5-nitro-imidazole A solution of 0.92 g of metallic sodium in 25 ml of methanol was introduced, while stirring, within 5 minutes, under an atmosphere of nitrogen at C, into a solution of g of S-(1-methyl-5-nitro-imidazolyl-2- methyl)-isothiouronium chloride (0.02 mole). The whole was stirred for minutes at 0 C. The colour of the solution changed during that time from yellow to light red brown. Then, 3.2 g of 2-chloro-5-nitro-pyri- 4.1 g of pale yellow crystals (69.5 of the theory) of 1-methyl-2-( 5 -nitropyridyl-2-thiomethyl )-5 nitroimidazole melting at 141 C were obtained.

Analysis: Calc. N 23.7 S 10.85 Found: N 23.5 S 10.6

We claim:

1. A (l-Alkyl-5-nitro-imidazolyl-2-alkyl)-pyridyl-sulfide, -sulf0xide or -sulfone of the formula I in which R represents methyl or ethyl, R represents a hydrogen atom or methyl, Z represents a sulfide group (S), a sulfoxide group (SO) or a sulfone group (SO which is linked with the pyridine ring in the 2-, 3- or 4-position, and in which R represents a halogen atom, a cyano or nitro group.

2. l-Methyl-2-(5-bromopyridyl-Z-thiomethyl-)-5- nitro-imidazole.

3. 1-Methyl-2-(5-cyanopyridyl-2-thiomethyl)-5- nitro-imidazole.

4. 1-Methyl2-(5-nitropyridyl-2-thiomethyl)-5-nitroimidazole. I

5. 1-Ethyl-2-(5-nitropyridyl-2-thiomethyl)-5-nitroimidazole.

6. 1-Methyl-2-[5-nitropyridyl-2-thio-( l-ethyl ]-5- nitroimidazole.

7. l-Methyl-2-(5-bromopyridyl-2-sulfinyl-methyl)-5- nitro-imidazole.

8. 1-Methyl-2-(5-bromopyridyl-2-sulfonyl-methyl)- S-nitro-imidazole. 

1. A (1-ALKYL-5-NITRO-IMIDAZOLYL-2-ALKYL)-PYRIDYL-SULFIDE, SULFOXIDE OR SULFONE OF THE FORMULA 1
 2. 1-Methyl-2-(5-bromopyridyl-2-thiomethyl-)-5-nitro-imidazole.
 3. 1-Methyl-2-(5-cyanopyridyl-2-thiomethyl)-5-nitro-imidazole.
 4. 1-Methyl-2-(5-nitropyridyl-2-thiomethyl)-5-nitro-imidazole.
 5. 1-Ethyl-2-(5-nitropyridyl-2-thiomethyl)-5-nitro-imidazole.
 6. 1-Methyl-2-(5-nitropyridyl-2-thio-(1-ethyl))-5-nitroimidazole.
 7. 1-Methyl-2-(5-bromopyridyl-2-sulfinyl-methyl)-5-nitro-imidazole.
 8. 1-Methyl-2-(5-bromopyridyl-2-sulfonyl-methyl)-5-nitro-imidazole. 